Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors.

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 µM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

MicroRNA-191 regulates oral squamous cell carcinoma cells growth by targeting PLCD1 via the Wnt/ß-catenin signaling pathway.

BACKGROUND: Studies have shown that microRNA-191 (miR-191) is involved in the development and progression of a variety of tumors. However, the function and mechanism of miR-191 in oral squamous cell carcinoma (OSCC) have not been clarified. METHODS: The expression level of miR-191 in tumor tissues of patients with primary OSCC and OSCC cell lines were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. OSCC cells were treated with miR-191 enhancers and inhibitors to investigate the effects of elevated or decreased miR-191 expression on OSCC cells proliferation, migration, cell cycle, and tumorigenesis. The target gene of miR-191 in OSCC cells were analyzed by dual-Luciferase assay, and the downstream signaling pathway of the target genes was detected using western blot assay. RESULTS: The expression of miR-191 was significantly upregulated in OSCC tissues and cell lines. Upregulation of miR-191 promoted proliferation, migration, invasion, and cell cycle progression of OSCC cells, as well as tumor growth in nude mice. Meanwhile, reduced expression of miR-191 inhibited these processes. Phospholipase C delta1 (PLCD1) expression was significantly downregulated, and negatively correlated with the expression of miR-191 in OSCC tissues. Dual-Luciferase assays showed that miR-191-5p could bind to PLCD1 mRNA and regulate PLCD1 protein expression. Western blot assay showed that the miR-191 regulated the expression of ß-catenin and its downstream gene through targeting PLCD1. CONCLUSION: MicroRNA-191 regulates oral squamous cell carcinoma cells growth by targeting PLCD1 via the Wnt/ß-catenin signaling pathway. Thus, miR-191 may serve as a potential target for the treatment of OSCC.

Rectangular Amplitude Mask-Based Auto-Focus Method with a Large Range and High Precision for a Micro-LED Wafer Defects Detection System.

Auto-focus technology plays an important role in the Micro-LED wafer defects detection system. How to accurately measure the defocus amount and the defocus direction of the Micro-LED wafer sample in a large linear range is one of the keys to realizing wafer defects detection. In this paper, a large range and high-precision auto-focus method based on a rectangular amplitude mask is proposed. A rectangular amplitude mask without a long edge is used to modulate the shape of the incident laser beams so that the spot shape distribution of the reflected laser beam on the sensor changes with the defocus amount of the wafer sample. By calculating the shape of the light spots, the defocus amount and the defocus direction can be obtained at the same time. The experimental results show that under the 20× microscopy objective, the linear range of the auto-focus system is 480 µm and the accuracy can reach 1 µm. It can be seen that the automatic focusing method proposed in this paper has the advantages of large linear range, high accuracy, and compact structure, which can meet the requirements of the Micro-LED wafer defects detection equipment.

Paternal exposure to arsenic and sperm DNA methylation of imprinting gene Meg3 in reproductive-aged men.

BACKGROUND: Prenatal exposure to arsenic and mercury have been associated with adverse pregnancy outcomes that might be in part mediated by dynamic modification of imprinting gene that are emerging mechanism. OBJECTIVES: The objective of this study was to examine the impacts of paternal exposure to arsenic and co-exposure to arsenic and mercury on human sperm DNA methylation status of imprinting genes, respectively. METHODS: A total of 352 male subjects (23-52 years old) were recruited and demographic data were obtained through questionnaires. Urinary arsenic and mercury levels were measured using hydride generation-atomic fluorescence spectrometer. Multivariate regression model was employed to investigate the relationship between urinary arsenic levels and sperm DNA methylation status at H19, Meg3 and Peg3, measured by pyrosequencing, and evaluating the interaction with mercury. RESULTS: After adjusting potential confounds factors by multivariate regression model, the results indicated a significantly positive relationship between urinary arsenic levels and the methylation status of Meg3 at both mean level (ß = + 0.125, p < 0.001) and all individual CpGs, i.e., CpG1 (ß = + 0.094, p < 0.001), CpG2 (ß = + 0.132, p < 0.001), CpG3 (ß = + 0.121, p < 0.001), CpG4 (ß = + 0.142, p < 0.001), CpG5 (ß = + 0.111, p < 0.001), CpG6 (ß = + 0.120, p < 0.001), CpG7 (ß = + 0.143, p < 0.001), CpG8 (ß = + 0.139, p < 0.001) of Meg3 DMRs. The interaction effects analysis indicated the interaction effects of arsenic and mercury on Meg3 were not existing. CONCLUSIONS: Paternal nonoccupational exposure to arsenic induces the altered DNA methylation status of Meg3 in human sperm DNA. In addition, the interaction effects of arsenic and mercury on Meg3 were not existing. These findings would implicate the sensibility of sperm epigenome for environmental pollutions.

Effects of Peripherally inserted Central Catheter (PICC) materials and designs on reduction of PICC-related complications: A systematic review and meta-analysis.

Studies showed that integrating coating or valve into Peripherally Inserted Central (PICC) can prevent related complications. However, data regarding efficiency were controversial. Therefore, a systematic review was needed to analyse the effect of PICC materials and designs on reduction of PICC-related complications. We searched PubMed, Cochrane library, EMbase, grey literature and referent literature from inception to 5 August 2022. Randomized controlled trials (RCTs) and case-control study were included. Two authors extracted data independently, using a predesigned Excel form, and assessed the quality of included RCTs according to the Cochrane Handbook for Systematic Reviews (V5.1.0), case-control study was assessed by the Newcastle-Ottawa Scale. Data were analysed using Review Manager (v5.3.0). A total of 10 RCTs and one case-control study were included. Meta-analysis results showed that PICC designs reduce the incidence of obstruction, and at the critical value of PICC-associated bloodstream infection, but may have no effects on other complications. Based on the literature reviewed, we can only say PICC new materials did not reflect significant reduction on complications, what's more, the result needs more multicentre, large RCTs to support. We suggested clinicians combine descriptive research and cost-effect analysis to select appropriate PICC materials and designs for patients.

Dexmedetomidine alleviates sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway in aged mice.

PURPOSE: Microglia-mediated inflammation is associated with perioperative neurocognitive disorders (PNDs) caused by sevoflurane. Dexmedetomidine has been reported to protect against sevoflurane-induced cognitive impairment. In this study, we investigated the effects and underlying mechanisms of dexmedetomidine on sevoflurane-induced microglial neuroinflammation and PNDs. METHODS: Wild-type and purinergic ionotropic 4 receptor (P2X4R) overexpressing C57/BL6 mice were intraperitoneally injected with 20 µg/kg dexmedetomidine or an equal volume of normal saline 2 h prior to sevoflurane exposure. The Morris water maze (MWM) test was performed to assess cognitive function. Immunofluorescence staining was employed to detect microglial activation. The expression levels of proinflammatory cytokines were measured by real-time quantitative PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The protein levels of P2X4R and NOD-like receptor protein 3 (NLRP3) were detected by Western Blotting. RESULTS: Sevoflurane increased the number of microglia, upregulated the levels of proinflammatory cytokines, elevated the protein levels of P2X4R and NLRP3 in the hippocampus and induced cognitive decline, while pretreatment with dexmedetomidine downregulated the protein levels of P2X4R and NLRP3, alleviated sevoflurane-induced microglial neuroinflammation and improved cognitive dysfunction. Moreover, overexpression of P2X4R weakened the neuroprotective effect of dexmedetomidine. CONCLUSIONS: Dexmedetomidine protected against sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway.

The relationship between post-traumatic stress and negative emotions in patients with breast cancer: the mediating role of emotion regulation.

Purpose:Negative emotions can adversely affect the treatment and recovery of breast cancer patients. Post-traumatic stress caused by cancer can increase the negative emotions of patients. This study assessed the relationship between post-traumatic stress and emotional regulation strategies, and the role of emotional regulation in the relationship between post-traumatic stress and negative emotions in breast cancer patients.Design:Cross-sectional questionnaire with sample of 214 Chinese women with breast cancerMethods:Participants completed the Impact of Event Scale-Revised, Hospital Anxiety and Depression Scale, and Emotion Regulation Questionnaire. Correlation and mediation analyses were conducted to assess associations among the scores of these scales.Findings:Patients with low post-traumatic stress chose cognitive reappraisal strategies, while those with high post-traumatic stress chose expressive suppression strategies. Cognitive reappraisal had a significant negative predictive effect on negative emotions, while expressive suppression had a significant positive predictive effect on patient's negative emotions.Conclusions:Cognitive reappraisal may reduce the impact of post-traumatic stress on negative emotions experienced by breast cancer patients. Implications for psychosocial providers or policy: Psychosocial workers in China should conduct cognitive reappraisal training for breast cancer patients with high negative emotions and severe post-traumatic stress. For Chinese breast cancer patients living in other regions, the local oncology social workers should take into account their cultural background and lack of expression, and encourage them to choose cognitive reappraisal strategies.

Synthesis and antiproliferative evaluation of novel 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives as potential anticancer agents.

Based on our previous work, a novel class of 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives were synthesized and evaluated as antiproliferative agents. Structure-activity relationship analysis revealed that the greatest activities were achieved with a 4-(4-methylpiperazin-1-yl)aniline group at C-2 position of dihydropteridin-6(5H)-one core, and the most promising compound 6k demonstrated comparable antiproliferative activity with Palbociclib and more potent than our parent derivative 4 toward four cell lines including HCT-116, HeLa, HT-29, and MDA-MB-231 with IC50 values of 3.29, 6.75, 7.56, and 10.30 µM, respectively. Moreover, the mechanism studies revealed that compound 6k could induce cell cycle arrest at G2/M phase via a concentration-dependent manner. In general, these preliminary observations suggested that these compounds could serve as promising scaffolds for further modification to develop novel and highly potent cancer therapy agents.

Development of pteridin-7(8H)-one analogues as highly potent cyclin-dependent kinase 4/6 inhibitors: Synthesis, structure-activity relationship, and biological activity.

CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 µM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.

Effects of ultrasound-guided techniques for radial arterial catheterization: A meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to evaluate whether ultrasound-guided techniques are superior compared to traditional palpation techniques in patients undergoing radial artery catheterization (RAC). METHODS: Electronic databases of PubMed, Embase, and the Cochrane Library were systematically searched to identify randomized controlled trials (RCTs). The relative risks (RRs) or weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were used to calculate the pooled effect estimates using the random effects model for categories and continuous data, respectively. RESULTS: A total of 19 RCTs comprising a total of 3220 individuals were selected for final analysis. The pooled RR suggested that ultrasound-guided techniques were associated with higher incidence of first attempt success than traditional palpation techniques (RR, 1.39; 95% CI, 1.21-1.59; P < 0.001). Moreover, we noted that ultrasound-guided techniques were associated with fewer mean attempts to success (WMD, -0.80 s; 95% CI, -1.35 to -0.25; P = 0.004) and a shorter mean time to success (WMD, -41.18 s; 95% CI, -75.43 to -6.93; P = 0.018) than traditional palpation techniques. Furthermore, individuals using ultrasound-guided techniques had a reduced risk of hematoma (RR, 0.40; 95% CI, 0.22-0.72; P = 0.003). CONCLUSIONS: This study indicated that ultrasound-guided techniques were superior compared to traditional palpation techniques for RAC in terms of efficacy and complications.

Genome-wide identification of chemosensory receptor genes in the small brown planthopper, Laodelphax striatellus.

The small brown planthopper (SBPH), Laodelphax striatellus is one of the major insect pests of rice, but little is known about the molecular-level means by which it locates its hosts. SBPH host-seeking behavior heavily relies on chemosensory receptors (CRs). In this study, we utilized genome analysis of the SBPH to identify 169 CRs, including: 133 odorant receptors (ORs), 13 gustatory receptors (GRs) and 23 ionotropic receptors (IRs). The phylogenetic relationships of OR genes from three rice planthoppers and other insect species revealed that the odorant co-receptor (Orco) clade is the most conserved group. Among the candidate GRs, two sugar receptors and five fructose receptors have been identified but no carbon dioxide receptors investigated. Furthermore, we identified homologs of the three highly conserved IR co-receptors. The obtained results will provide us with precious information needed to better understand the interaction between insect pests and crop plants required for effective crop protection.

The benefits of expressive writing among newly diagnosed mainland Chinese breast cancer patients.

The study aimed to evaluate the effects of an expressive writing intervention on quality of life (QoL) among mainland Chinese breast cancer patients. A total of 118 Chinese breast cancer patients were randomly assigned to one of four groups: a cancer-facts writing condition (CTL group), an emotional disclosure writing condition (EMO group), a self-regulation writing condition (SR group), or a neutral control condition with no writing tasks (CON group). QoL was assessed by FACT-B at baseline, 3-, and 6-month follow-ups. A repeated measure analysis of variance revealed significant effects of time (F = 13.9, P < 0.001, η2 = 0.20) and the time × group interaction (F = 3.5, P < 0.01, η2 = 0.08) on QoL. Residualized change models showed that the CTL, EMO and SR groups reported higher levels of QoL than the CON group at the 6-month follow-up. The EMO group had a higher level of QoL than the SR group. The CTL group had higher level of physical well-being compared to the SR group. Mainland Chinese breast cancer patients shortly after diagnosis benefit from expressive writing. They benefited more from cancer-facts and emotional disclosure compared to self-regulation. The study indicated that the impact of expressive writing may differ due to stage of cancer survivorship, social, and cultural context.

Molecular characterization and functional analysis of a novel candidate of cuticle carboxylesterase in Spodoptera exigua degradating sex pheromones and plant volatile esters.

Odorant-degrading enzymes (ODEs) are considered to play key roles in odorant inactivation to maintain the odorant receptor sensitivity of insects. Some members of carboxylesterase (CXE) is a major sub-family of ODEs. However, only a few CXEs have been functionally characterized so far. In the present study, we cloned the antennal esterase SexiCXE11 cDNA full-length sequences from the male antennae of a notorious crop pest, Spodoptera exigua, and its encoded 538 amino acids. It was similar to other insect esterases and had the characteristics of a carboxylesterase. We expressed recombinant enzyme in High-Five insect cells and obtained the high level purified recombinant protein by affinity column. Furthermore we test enzyme activity toward its two acetate sex pheromone components (Z9,E12-Tetradecadienyl acetate, Z9E12-14:Ac and Z9-Tetradecenyl acetate, Z9-14:Ac) and other 18 ester plant volatiles. Our results demonstrated that SexiCXE11 degraded acetate sex pheromone components with similar degradation activities (about 15.75% with Z9E12-14:Ac and 19.28% with Z9-14:Ac) and plant volatiles with a relatively high activity such as pentyl acetate and (Z)-3-hexenyl caproate. SexiCXE11 had high hydrolytic activity with these two ester odorants (>50% degradation), which is characterized that although a ubiquitous expression esterase SexiCXE11 may be partly involved with olfaction. This study may facilitate a better understanding of moth ODE differentiation and suggest strategies for the development of new pest behavior inhibitors.

Top 100 most-cited articles on tau protein: a bibliometric analysis and evidence mapping.

Background: Tau, a microtubule-associated protein extensively distributed within the central nervous system (CNS), exhibits close associations with various neurodegenerative disorders. Here, we aimed to conduct a qualitative and quantitative bibliometric study of the top 100 most-cited publications on tau protein and reveal the current research hotspots and future perspectives. Methods: The relevant literature was retrieved from the Web of Science Core Collection. CiteSpace (v6.2.R4) and VOSviewer (1.6.19) were adopted for bibliometric analysis with statistical and visual analysis. Results: Citations per article ranged from 615 to 3,123, with a median number of 765.5 times. "Neuroscience" emerged as the most extensively researched subject in this field. The USA has emerged as the leading country, with a publication record (n = 65), total citations (n = 66,543), strong centrality (0.29), and extensive international collaborations. Harvard University (n = 11) and the University of California, San Francisco (n = 11) were the top two institutions in terms of publications. Neuron dominated with 13 articles in the 37 high-quality journals. M. Goedert from the MRC Laboratory of Molecular Biology was the most productive (n = 9) and top co-cited (n = 179) author. The most frequently studied keywords were Alzheimer's disease (n = 38). Future research is anticipated to intensify its focus on the pathogenesis of various tau-related diseases, emphasizing the phosphorylation and structural alterations of tau protein, particularly in Alzheimer's disease. Conclusion: The pathogenesis of various tau-related diseases, including the phosphorylation and structural alterations of the tau protein, will be the primary focus of future research, with particular emphasis on Alzheimer's disease as a central area of investigation.

Mapping Theme Trends and Research Frontiers in Dexmedetomidine Over Past Decade: A Bibliometric Analysis.

Background: Dexmedetomidine, an α2-adrenergic receptor (α2-AR) agonist, is extensively used in clinical and animal studies owing to its sedative, analgesic, and anxiolytic effects. The diverse range of research domains associated with dexmedetomidine poses challenges in defining pivotal research directions. Therefore, this study aimed to conduct a qualitative and quantitative bibliometric study in the field of dexmedetomidine over the past decade to establish current research trends and emerging frontiers. Methods: Relevant publications in the field of dexmedetomidine between 2014 and 2023 were extracted from the Web of Science Core Collection database. The bibliometric analysis, incorporating statistical and visual analyses, was conducted using CiteSpace (6.1.R6) and R (4.3.1). Results: The present study encompassed a total of 5,482 publications, exhibiting a consistent upward trend over the past decade. The United States and its institutions had the highest centrality. Ji, Fuhai, and Ebert, Thomas J. were identified as the most productive author and the most cited author, respectively. As anticipated, the most cited journal was Anesthesiology. Moreover, cluster analysis of cited references and co-occurrence of keywords revealed that recent studies were primarily focused on sedation, delirium, and opioid-free anesthesia. Finally, a timeline view of keywords clusters and keywords burst demonstrated that primary research frontiers were stress response, neuroinflammation, delirium, opioid-free anesthesia, peripheral nerve block, and complications. Conclusion: Current research trends and directions are focused on sedation, delirium, and opioid-free anesthesia, as evidenced by our results. The frontier of future research is anticipated to encompass basic investigations into dexmedetomidine, including stress response and neuroinflammation, as well as clinical studies focusing on delirium, opioid-free anesthesia, peripheral nerve block, and associated complications.

Synthesis of benzooxepane-fused cyclobutene derivatives via Pd-catalyzed cascade reactions of haloarenes and diynylic ethers.

A tandem palladium-catalyzed Sonogashira coupling, propargyl-allenyl isomerization, and [2+2] cycloaddition sequence between electron-deficient haloarenes and 1,8-diynylic ethers is developed. The reaction shows good functional tolerance and proceeds under mild conditions to provide a new profile of benzooxepane-fused cyclobutene derivatives in moderate to high yields with high selectivity. The reaction mechanism is validated both by experimental studies and DFT calculations.

The relationship between psychological distress and cognitive failure among breast cancer survivors: a network analysis.

Background: Psychological distress is highly prevalent and has a severe impact on the quality of life among breast cancer survivors. This type of distress is associated with cognitive failure. However, previous studies have focused solely on the total scale scores of these two concepts while ignoring the unique relationship between specific components. In the present study, we utilized network analysis to explore the relationship between psychological distress and cognitive failure in breast cancer survivors. Methods: The network analysis approach was adopted to estimate the regularized partial correlation network in a cross-sectional sample of 409 breast cancer survivors. All participants were assessed using the Depression Anxiety Stress Scale and the Cognitive Failure Questionnaire. The Gaussian Graphical Model was employed to estimate the network, centrality indices, and edge weights, providing a description of the characteristics of the network. Results: The results indicated that anxiety-stress and depression-stress were the strongest edges in the community of psychological distress. Distractibility-memory was the strongest edge in the community of cognitive failure. Distractibility and memory were the most central nodes, with the highest expected influence in the network. Depression and motor coordination acted as important bridge nodes with the highest bridge expected influence. Conclusion: Distractibility and memory in cognitive failure played important roles in activating and maintaining the relationship network. Motor coordination was identified as the crucial pathway for the impact of cognitive failure on psychological distress. Interventions targeting these specific issues might be more effective in improving cognitive failure and reducing psychological distress among breast cancer survivors.

A label-free LC/MS-based enzymatic activity assay for the detection of PDE5A inhibitors.

Phosphodiesterase type 5 (PDE5), a cyclic nucleotide phosphodiesterase, controls the duration of the cyclic guanosine monophosphate (cGMP) signal by hydrolyzing cGMP to GMP. Inhibiting the activity of PDE5A has proven to be an effective strategy for treating pulmonary arterial hypertension and erectile dysfunction. Current enzymatic activity assay methods for PDE5A mainly use fluorescent or isotope-labeled substrates, which are expensive and inconvenient. Here, we developed an LC/MS-based enzymatic activity assay for PDE5A without labeling, which detects the enzymatic activity of PDE5A by quantifying the substrate cGMP and product GMP at a concentration of 100 nM. The accuracy of this method was verified by a fluorescently labeled substrate. Moreover, a new inhibitor of PDE5A was identified by this method and virtual screening. It inhibited PDE5A with an IC50 value of 870 nM. Overall, the proposed strategy provides a new method for screening PDE5A inhibitors.

Paeoniflorin, the Main Monomer Component of Paeonia lactiflora, Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation.

OBJECTIVE: To explore the mechanism of paeoniflorin (PF) on osteoarthritis (OA) synovial inflammation from network pharmacology to experimental pharmacology. METHODS: Targets of OA were constructed by detecting the database of network database platforms (Therapeutic Target database, DrugBank and GeneCards), and the targets of PF were constructed by PubChem and Herbal Ingredients' Targets database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these co-targeted genes were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, and protein-protein interaction (PPI) networks were conducted via the search tool for the retrieval of interacting genes (STRING) database. Cell counting kit-8 (CCK-8) assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes (FLS), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot were used to verify the potential mechanism of PF in synovial inflammation. RESULTS: Twenty-six co-targeted genes were identified. GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm, and the biological processes mainly involved 'cellular response to hypoxia' 'lipopolysaccharide (LPS)-mediated signaling pathway' and 'positive regulation of gene expression'. KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with 'hypoxia-inducible factor-1 (HIF-1) signaling pathway' and 'tumor-necrosis factor (TNF) signaling pathway'. The PPI network showed that the top 3 hub genes were TP53, TNF, and CASP3. Molecular docking results showed that PF was well docking with TNF. CCK-8 showed no potential toxicity of 10, 20 and 50 µmol/L PF on human OA FLS. And PF significantly decreased the expression levels of interleukin-1 ß, interleukin-6, TNF-α matrix metalloproteinase 13 (MMP13), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and TNF-α in LPS-induced OA FLS. CONCLUSION: PF exhibited potent anti-inflammatory effect in OA synovial inflammation.